Damdinsuren Bazarragchaa, Nagano Hiroaki, Kondo Motoi, Yamamoto Hirofumi, Hiraoka Nobuaki, Yamamoto Tameyoshi, Marubashi Shigeru, Miyamoto Atsushi, Umeshita Koji, Dono Keizo, Nakamori Shoji, Wakasa Ken-Ichi, Sakon Masato, Monden Morito
Department of Surgery and Clinical Oncology, Graduate School of Medicine, Osaka University, Osaka, Japan.
Int J Oncol. 2005 Feb;26(2):319-27.
Several studies reported that Id (Inhibitor of DNA binding or Differentiation) proteins, helix-loop-helix transcription factors, have important roles in differentiation, cell cycle and angiogenesis in various cells. However, the role of Id proteins in hepatocellular carcinoma (HCC) remains unclear. We examined the immunohistochemical expression of Id1, Id2 and Id3 proteins in 54 surgically resected HCCs with surrounding HCV or HBV-related chronic hepatitis (n=30) and liver cirrhosis (n=24). All non-cancerous livers exhibited immunoreactivity for Id proteins and the expression increased from chronic hepatitis to cirrhosis. In HCCs (n=45), well-differentiated tumors mostly exhibited strong or moderate immunostaining for all Id proteins, while proportion of the samples with weak or no expression increased with tumor dedifferentiation and frequently observed in poorly (66.7, 93.3 and 93.3% respectively for Id1, 2, 3) or undifferentiated (100% for all Ids) HCCs. Clinicopathological survey demonstrated a significant correlation between Id1, 2 and 3 expression and differentiation of carcinoma (p=0.0044, 0.0014 and 0.0014, respectively) although univariate analysis indicated that high expression of Id1 was significant predictive factor for longer disease-free survival of the patients (p=0.047). A similar tendency was also observed with Id2 and Id3. The present study demonstrate high expression of Id1, 2 and 3 in well-differentiated HCC and low expression in advanced dedifferentiated HCC, in contrast to its continuous expression during breast, prostate and colon carcinogenesis. These findings suggested that Id1, 2 and 3 might play a role in the early stages of hepatocarcinogenesis, but not in the development of advanced carcinoma, and might consequently be related to HCC dedifferentiation.
多项研究报道，Id（DNA结合抑制因子或分化抑制因子）蛋白，即螺旋-环-螺旋转录因子，在多种细胞的分化、细胞周期和血管生成中发挥重要作用。然而，Id蛋白在肝细胞癌（HCC）中的作用仍不清楚。我们检测了54例手术切除的HCC中Id1、Id2和Id3蛋白的免疫组化表达，这些病例伴有周围HCV或HBV相关慢性肝炎（n = 30）和肝硬化（n = 24）。所有非癌性肝脏均显示Id蛋白免疫反应性，且表达从慢性肝炎到肝硬化逐渐增加。在HCC（n = 45）中，高分化肿瘤大多对所有Id蛋白表现出强或中度免疫染色，而弱表达或无表达样本的比例随肿瘤去分化增加，且在低分化（Id1、2、3分别为66.7%、93.3%和93.3%）或未分化（所有Id均为100%）HCC中经常观察到。临床病理调查显示Id1、2和3的表达与癌的分化之间存在显著相关性（分别为p = 0.0044、0.0014和0.0014），尽管单因素分析表明Id1高表达是患者无病生存期较长的显著预测因素（p = 0.047）。Id2和Id3也观察到类似趋势。本研究表明，与Id蛋白在乳腺癌、前列腺癌和结肠癌发生过程中的持续表达相反，Id1、2和3在高分化HCC中高表达，而在晚期去分化HCC中低表达。这些发现提示Id1、2和3可能在肝癌发生的早期阶段起作用，但在晚期癌的发展中不起作用，因此可能与HCC去分化有关。
